Alcohol dependence (AD) is a major public health problem with a paucity of available treatments. The development of novel drugs with larger effect sizes to treat AD is a NIAAA priority. The purpose of this competing continuation is to identify new medications to treat protracted abstinence in AD while at the same time developing and validating a translational approach to screening potential medications that will move the field forward. Protracted abstinence involves a state of heightened relapse vulnerability following acute alcohol withdrawal that is driven by dysregulation in stress and reward systems in the CNS. In the previous funding period, significant progress was made in developing animal and human models of protracted abstinence with sensitivity to drug effects that were validated by efficacy outcomes in Phase II and III clinical trials of acamprosate, duloxetine, gabapentin, naltrexone and pregabalin. As next steps in model development for protracted abstinence (Specific Aim 1-preclinical, Specific Aim 3-human), our human cue reactivity model will be further developed to include stress-induced craving to more comprehensively assess medication efficacy for protracted abstinence. Animal models of cue- and stress- induced reinstatement will be refined in dependent and binge-drinking animals, to more closely parallel the human condition of AD. As next steps in medication development (Specific Aim 2-preclinical, Specific Aim 4-human) we have identified 5 drugs (aprepitant, levetiracetam, zonisamide, oxcarbazepine, prazosin) hypothesized to normalize the dysregulated brain systems related to the negative emotional states and craving associated with protracted abstinence that will be assessed for potential drug efficacy in our translational models. Additional drugs selected for preclinical studies represent a pipeline of desirable targets that may become available for human studies. The overall hypothesis under test is that animal and human models chosen will provide efficient, reliable and differential screens for the treatment potential of specific drugs for reducing relapse risk in protracted abstinence. Dynamic feedback from the animal and human components, and clinical trial data as it becomes available, will facilitate further development of these models. A critical aspect of the present proposal is the proposed dynamic feedback from the animal component and the clinical component, both of which are designed to streamline information and provide converging evidence for ultimate clinical use. The present proposal provides an advanced tier of screening that will allow identification of treatments for AD and endpoints likely to succeed in clinical trials. PUBLIC HEALTH RELEVANCE: The purpose of this Renewal Application is to develop theory-driven, empirically-validated, translational models of multiple phases of the alcoholism cycle to serve as rapid and efficient screens of potential pharmacotherapies for alcohol dependence. The results of these experiments may provide starting points for further clinical evaluation of selected compounds and for identifying endpoints likely to show drug efficacy in Phase II clinical trials. The development of converging preclinical and human models and feedback from preclinical and human laboratory studies is designed to mitigate the discrepancy that often occurs between preclinical expectations and clinical outcomes in medication development.